Characterizing the pathogenesis and targeted therapeutics of Wilms' Tumor 1 (WT1) mutations in AML

描述 AML 中 Wilms 肿瘤 1 (WT1) 突变的发病机制和靶向治疗

• 批准号: 9898335
• 负责人: Haijiao Zhang
• 金额: $ 10.21万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9898335
• 关键词: Acute; Advisory Committees; Apoptosis; BCL2 gene; Bioinformatics; Biological Assay; Bone Marrow; Bone Marrow Cells; Bone Marrow Stem Cell; C-terminal; CEBPA gene; CRISPR screen; CSF3R gene; Candidate Disease Gene; Caring; Cell Line; Cell Lineage; Cell Proliferation; Cells; Clinic; Clustered Regularly Interspaced Short Palindromic Repeats; Colony-Forming Units Assay; Combined Modality Therapy; Cytarabine; Cytogenetics; Data; Development; Dimerization; Disease; Disease Progression; Dose; Drug resistance; Drug usage; Engineering; Exons; FLT3 gene; FLT3 inhibitor; Faculty; Frameshift Mutation; Genes; Goals; Growth; Hematologic Neoplasms; Hematopoietic stem cells; Human; Inbred BALB C Mice; Leukemic Cell; Manuscripts; Mediating; Medical; Medical Students; Mentors; Mentorship; Modality; Modeling; Molecular; Monitor; Mus; Mutation; Myeloid Leukemia; N-terminal; Oncogenes; Oncogenic; Outcome; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phenotype; Positioning Attribute; Preparation; Publishing; RNA; Recurrent disease; Refractory; Regulatory Element; Research; Research Personnel; Resistance; Sampling; Series; Structure; Sum; Therapeutic; Training; Transcriptional Regulation; Translations; Transplantation; Tyrosine Kinase Domain; WT1 gene; Xenograft procedure; Zinc Fingers; career; chemotherapy; clinical predictors; clinically relevant; combinatorial; deep sequencing; disease phenotype; drug candidate; drug sensitivity; functional genomics; gene therapy; genome editing; genome-wide; in vivo; inhibitor/antagonist; leukemia; leukemia treatment; leukemic stem cell; loss of function; mouse model; mutant; myeloid leukemia cell; novel therapeutics; outcome forecast; overexpression; progenitor; receptor; resistance mechanism; resistance mutation; screening; standard care; stem cell biology; targeted cancer therapy; targeted treatment; therapeutic target; transcription factor; transcriptome sequencing; translational medicine; variant of unknown significance

PROJECT SUMMARY/ABSTRACT Dr. Haijiao Zhang has been training as a medical student for 7 years with a focus on hematological malignancies and as a researcher for 6 years in the field of characterizing oncogene and drug resistance mechanisms. Her research has led to 8 published manuscripts and 4 other manuscripts in submission /preparation. The theme of Dr. Zhang's research involves systematic characterization of leukemia oncogenes and understanding leukemia drug resistance mechanisms. She has characterized 4 distinct mechanisms of CSF3R mutations and diverse mechanisms associated with drug resistance to the FLT3 inhibitor crenolanib. The WT1 (Wilms' tumor 1) gene encodes a transcription factor with C-terminal zinc-finger domains, whereas the N-terminal part contains domains that mediate receptor dimerization, RNA recognition, and transcriptional regulation. WT1 mutations are present in approximately 10–15% of AML and are associated with chemotherapy resistance and disease relapse. WT1 mutations are frameshift mutations or substitutions across all structural domains, predominantly in exons 7 and 9. The pathogenesis mediated by loss-of-function of WT1 zinc finger domain mutations has been studied; however very little is known about the oncogenic potential, drug sensitivity, and the structural basis of mutations residing in other domains of WT1. In the current proposal, Dr. Zhang will evaluate the functional consequences of these mutations and characterize the mechanisms associated with the growth/survival advantage and a higher propensity for chemotherapy resistance of WT1 mutations. She also aims to identify therapeutics with enhanced efficacy in the WT1 mutant setting. Using ex vivo inhibitor screening on primary leukemia patient samples, she has determined that inhibitors of BCL2 and RAF/ERK pathways demonstrated higher efficacy against WT1 mutant samples compared with controls. She will validate these findings using NRG mouse model. Finally, she will investigate the phenotypic, mechanistic, and therapeutics targeting WT1 combinatorial mutation. Dr. Zhang's long-term career goals include the establishment of an independent research lab focusing on systematic characterization of oncogenic mutations and chemotherapy resistance to better predict the clinical relevance of mutations and identify novel therapeutics to circumvent chemotherapy resistance. During the mentored phase, she will continue to receive excellent mentorship from Dr. Jeffrey Tyner, an expert on functional genomics and targeted therapy. She will receive co-mentorship from Dr. Ravi Majeti, an expert in leukemia stem cell biology, CRISPR editing, and high-fidelity xenotransplantation mouse models, which she will use in the current project. The proposed research will also be enhanced by guidance from Dr. Brian Druker, a pioneer in translational medicine and targeted therapies for cancer; and Dr. Shannon McWeeney who will provide guidance in bioinformatics analyses. Additionally, Dr. Tyner, Dr. Majeti, and the advisory team will assist her in navigating the transition to an independent faculty position.

项目摘要/摘要 Haijiao Zhang博士一直在医学生培训7年，重点是血液学 在表征癌基因和耐药性的领域中，Malignancys和研究人员已有6年 机制。她的研究导致了8个出版的手稿和其他4项手稿。 /准备。张博士研究的主题涉及白血病的系统表征 并了解白血病耐药性机制。她表征了4种不同的机制 CSF3R突变和与FLT3抑制剂耐药性耐药性相关的不同机制。 WT1（Wilms的肿瘤1）基因编码具有C末端锌指域的转录因子，而 N末端部分包含介导受体二聚化，RNA识别和转录的域 规定。 WT1突变在大约10-15％的AML中呈现，与 化学疗法抗性和疾病缓解。 WT1突变是移码突变或跨越的取代 所有结构结构域，主要在外显子7和9中。 锌指域突变已研究；然而，关于致癌潜力的知之甚少 药物敏感性以及位于WT1其他领域的突变的结构基础。在当前的提议中 张博士将评估这些突变的功能后果，并表征机制 与生长/生存优势和WT1化学疗法抗性的可靠性相关 突变。她还旨在确定在WT1突变体环境中效率提高的治疗。使用ex 在原发性白血病患者样本上筛查体内抑制剂，她确定BCl2和 与对照组相比，RAF/ERK途径对WT1突变样品的效率更高。她 将使用NRG鼠标模型验证这些发现。最后，她将研究表型，机械性 和靶向WT1组合突变的治疗。 张博士的长期职业目标包括建立一个关注的独立研究实验室 致癌突变和化学疗法耐药性的系统表征可以更好地预测临床 突变的相关性并确定新的疗法以规避化学疗法的抗性。 在修订阶段，她将继续从专家杰弗里·泰纳（Jeffrey Tyner）博士那里获得出色 关于功能性基因组学和靶向治疗。她将获得Ravi Majeti博士的会议，专家 白血病干细胞生物学，CRISPR编辑和高保真异种移植小鼠模型 将用于当前项目。拟议的研究还将通过Brian Druker博士的指导来增强 翻译医学和靶向癌症疗法的先驱；还有Shannon McWeeney博士 在生物信息学分析中提供指导。额外 协助她导航过渡到独立教师职位。